U.S. patent application number 15/721259 was filed with the patent office on 2018-01-25 for topical pharmaceutical composition based on semifluorinated alkanes.
This patent application is currently assigned to NOVALIQ GMBH. The applicant listed for this patent is Bernhard Gunther, Dieter Scherer, Bastian Theisinger, Sonja Theisinger. Invention is credited to Bernhard Gunther, Dieter Scherer, Bastian Theisinger, Sonja Theisinger.
Application Number | 20180021434 15/721259 |
Document ID | / |
Family ID | 46168482 |
Filed Date | 2018-01-25 |
United States Patent
Application |
20180021434 |
Kind Code |
A1 |
Gunther; Bernhard ; et
al. |
January 25, 2018 |
TOPICAL PHARMACEUTICAL COMPOSITION BASED ON SEMIFLUORINATED
ALKANES
Abstract
The invention provides liquid or semi-solid pharmaceutical
compositions for topical administration comprising a
semifluorinated alkane. The compositions are useful for the
delivery of active ingredients into the deep layers of the skin or
skin appendages. Various active ingredients may be incorporated,
such as immunosuppressants, antiinfectives, antifungal agents,
antiinflammatory agents, and retinoids.
Inventors: |
Gunther; Bernhard;
(Dossenheim, DE) ; Theisinger; Bastian; (Mannheim,
DE) ; Theisinger; Sonja; (Mannheim, DE) ;
Scherer; Dieter; (Laufen, CH) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Gunther; Bernhard
Theisinger; Bastian
Theisinger; Sonja
Scherer; Dieter |
Dossenheim
Mannheim
Mannheim
Laufen |
|
DE
DE
DE
CH |
|
|
Assignee: |
NOVALIQ GMBH
Heidelberg
DE
|
Family ID: |
46168482 |
Appl. No.: |
15/721259 |
Filed: |
September 29, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14122044 |
Nov 25, 2013 |
|
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PCT/EP2012/059787 |
May 24, 2012 |
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15721259 |
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Current U.S.
Class: |
514/29 ; 514/291;
514/759; 514/772 |
Current CPC
Class: |
A61P 37/08 20180101;
A61P 29/00 20180101; A61K 31/436 20130101; A61P 17/10 20180101;
A61K 31/355 20130101; A61P 17/00 20180101; A61K 47/06 20130101;
A61K 9/08 20130101; A61K 9/0014 20130101; A61K 9/1075 20130101;
A61P 17/12 20180101; A61P 31/04 20180101; A61P 31/10 20180101; A61P
31/12 20180101; A61P 17/04 20180101; A61K 45/06 20130101; A61P
17/06 20180101; A61P 17/14 20180101; A61P 37/06 20180101; A61P
17/02 20180101 |
International
Class: |
A61K 45/06 20060101
A61K045/06; A61K 31/355 20060101 A61K031/355; A61K 9/08 20060101
A61K009/08; A61K 31/436 20060101 A61K031/436; A61K 9/107 20060101
A61K009/107; A61K 9/00 20060101 A61K009/00; A61K 47/06 20060101
A61K047/06 |
Foreign Application Data
Date |
Code |
Application Number |
May 25, 2011 |
EP |
11167552.6 |
May 26, 2011 |
EP |
11167732.4 |
Claims
1-15. (canceled)
16. A method for delivering an active ingredient to layers of the
skin below the stratum corneum comprising the step of topically
administering to the skin a topical pharmaceutical composition
comprising an effective amount of an active ingredient and a
semifluorinated alkane according to formula RFRH wherein RF is a
linear perfluorinated hydrocarbon segment with 4 to 12 carbon
atoms, and RH is a linear alkyl group with 4 to 8 carbon atoms.
17. The method of claim 16, wherein the active ingredient is
delivered to the vital epidermis, the dermis and/or the
hypodermis.
18. The method of claim 16, wherein the semifluorinated alkane is
selected from F4H5, F4H6, F4H8, F6H6 and F6H8, wherein F means a
perfluorinated hydrocarbon segment, H means a non-fluorinated
segment, and the number is the number of carbon atoms of the
respective segment.
19. The method of claim 16, wherein the composition is in the form
of a liquid or semisolid solution, emulsion, or microemulsion.
20. The method of claim 16, wherein the composition comprises a
physiologically acceptable co-solvent selected from ethanol,
acetone, ethyl acetate, isopropyl alcohol, glycerol, propylene
glycol, pentylene glycol, polyethylene glycol, liquid paraffin,
triglyceride oils, hydrofluorocarbons such as HFA 134a and/or HFA
227, and liquid mono- or diglycerides.
21. The method of claim 16, wherein the skin is affected by a
disease or condition selected from psoriasis, dermatitis, erythema,
eczema, allergy, acne, actinic keratosis, fungal infections,
bacterial infections, viral infections, verrucae, or rosacea.
22. The method of claim 16, wherein the skin is affected by
psoriasis, and wherein the active ingredient is selected from
immunosuppressants or retinoids.
23. The method of claim 22, wherein the immunosuppressant is
selected from tacrolimus, sirolimus, everolimus, tacrolimus,
pimecrolimus, ridaforolimus, temsirolimus, zotarolimus, and
ciclosporin A.
24. The method of claim 22, wherein the retinoid is selected from
retinol, retinal, tretinoin, isotretinoin, alitretinoin,
etretinate, acitretin, tazarotene, bexarotene and adapalene.
25. The method of any of claim 16, wherein the skin is affected by
acne, and wherein the active ingredient is selected from retinoids
or anti-infective agents.
26. The method of claim 25, wherein the retinoid is selected from
retinol, retinal, tretinoin, isotretinoin, alitretinoin,
etretinate, acitretin, tazarotene, bexarotene and adapalene.
27. The method of claim 25, wherein the anti-infective agents is
selected from azithromycin, erythromycin, clindamycin, or
minocycline.
28. The method of claim 16, wherein the skin is affected by actinic
keratosis, and wherein the active ingredient is selected from
diclofenac, 5-fluorouracil and imiquimod.
29. The method of claim 16, wherein the skin is affected by a
cutaneous disease involving symptoms related to inflammatory
responses and the active ingredient is a corticosteroid.
30. The method of claim 16, wherein the skin is affected by pain or
itching and the active ingredient is a local anesthetic agent.
31. The method of claim 16, wherein the skin is affected by is a
fungal infection and the active ingredient is an anti-fungal
agent.
32. The method of claim 16, wherein the skin is affected by a viral
infection, and the active ingredient is an anti-viral agent.
33. The method of claim 16, wherein i. at least about 5% of the
topically administered amount of active ingredient is delivered to
the vital epidermis within about 30 minutes, or ii. at least about
5% of the topically administered amount of active ingredient is
delivered to the dermis within about 30 minutes; or iii. at least
about 10% of the topically administered amount of active ingredient
is delivered to the dermis within about 30 minutes; or iv. at least
about 5% of the topically administered active ingredient is
delivered to the hypodermis within about 30 minutes; or v. at least
about 10% of the topically administered active ingredient is
delivered to the hypodermis within about 30 minutes.
34. The method of claim 16, wherein at least about 15% of the
topically administered active ingredient is delivered to a depth of
at least 10 .mu.m within about 30 minutes.
35. The method of claim 16, wherein at least about 20% of the
topically administered active ingredient is delivered to a depth of
at least 10 .mu.m within about 30 minutes.
36. The method of claim 16, wherein at least about 10% or at least
15% or at least about 20% of the topically administered active
ingredient is delivered to a depth of at least 100 .mu.m within
about 30 minutes.
Description
BACKGROUND OF THE INVENTION
[0001] The present invention is in the field of pharmacotherapy.
More specifically, it relates to the treatment of diseases and
conditions affecting the skin and skin appendages.
[0002] The pharmacological treatment of cutaneous disorders may
involve systemic or local administration of an effective
medicament. Typically, whenever local (e.g. epicutaneous)
administration is possible and leads to the desired outcome, it is
preferred over systemic therapy which is, quite plausibly, more
often associated with adverse systemic effects. However, effective
treatment via the topical route of administration requires that the
drug substance is soluble in, and/or otherwise compatible with a
suitable carrier or vehicle, and that it reaches its target tissue
layer(s) in an effective amount or concentration. In fact, in some
cases, effective epicutaneous treatment is particularly difficult
to achieve.
[0003] The skin consists of three main layers--the epidermis, the
dermis and the hypodermis. The epidermis comprises the stratum
corneum (the outermost superficial layer of skin, consisting of
dead cells) and the vital (living) epidermis. Depending on the
cutaneous disease or condition, one or more layers of the skin may
become affected. In some dermatological conditions, such as
ichthyosis, callus, or plaque psoriasis, the stratum corneum is
thicker than in the healthy state and can provide a significantly
greater barrier to the penetration of a therapeutical compound,
thus reducing its efficacy in the treatment of the deeper layers of
the skin. Moreover, it has been shown recently that with increasing
age, the skin of a human also becomes more resistant to the
penetration by drug substances.
[0004] The use of penetration enhancers has been proposed in order
to achieve a sufficient and consistent availability of various
therapeutic compounds at the site of action during the treatment of
cutaneous diseases. For example, U.S. Pat. No. 5,326,566 describes
a composition of a pharmacological agent in combination with
dibutyl adipate, or a mixture of dibutyl adipate and isopropyl
myristate, which could enhance the penetration through the skin and
even increase the amount absorbed into the systemic circulation, if
that is desired.
[0005] Even though a variety of penetration enhancers have been
used for enhancing the absorption of therapeutic agents into and
through the skin, substantial problems may arise when the
penetration enhancers are incompatible with a particular drug
substance, leading to drug instability and degradation into
potentially harmful degradants.
[0006] US 2005/0079210 A1 proposes the use of liposomes the
epicutaneous administration of drugs and cosmetically useful
agents. However, liposomes are difficult to manufacture
cost-effectively and in a reproducible manner.
[0007] Other novel formulation strategies for topical medications
require the occlusion of the skin after administration, which is
however perceived as inconvenient by many patients
[0008] EP0670159A1 discloses stable oily emulsions comprising
surfactant and semifluorinated alkane, which are proposed to be
suitable for transporting oxygen to the skin or vascular system or
for use as a standard for blood-gas analysis. The use of these
compositions as carriers of active agent was also suggested,
although no mention is made of whether these compositions are
capable of effectively delivering active agents in particular to
the deeper layers of the skin.
[0009] There clearly remains a need for pharmaceutical formulations
and vehicles which allow the effective treatment of cutaneous
disorders by topical administration. It is therefore an object of
the present invention to provide such improved compositions which
overcome one or more disadvantages of known compositions. In
particular, it is an object of the invention to provide
compositions of topically active drug substances which are
effective and convenient. Further objects of the invention will
become clear on the basis of the description of the invention
below, including the examples, and of the patent claims.
SUMMARY OF THE INVENTION
[0010] The present invention provides a novel pharmaceutical
composition for administration to the skin or a skin appendage. The
composition comprises an effective amount of an active ingredient
and a semifluorinated alkane (SFA) according to formula RFRH or
RFRHRF, wherein RF is a perfluorinated hydrocarbon segment with 20
or less carbon atoms and RH is a non-fluorinated hydrocarbon
segment with 3 to 20 carbon atoms. In a preferred embodiment, the
SFA is selected from F4H5, F4H6, F4H8, F6H6 and F6H8.
[0011] It has been surprisingly found by the inventors that SFAs
are capable of delivering active pharmaceutical ingredients
effectively into the deeper layers of the skin, i.e. into the vital
layers below the stratum corneum of the epidermis. Moreover, they
are capable of delivering active ingredients deep into nails.
[0012] The composition may, for example, be in the form of a
solution or an emulsion. They are useful for administering a wide
range of topical agents indicated in a number of cutaneous diseases
and conditions.
BRIEF DESCRIPTION OF THE DRAWINGS
[0013] FIG. 1 shows the amount of tacrolimus found in different
layers of the skin (SC=stratum corneum; EP=vital epidermis;
DR=dermis; AK=hypodermis) 30 min, 300 min, and 1,000 min after
administration as an SFA-based formulation to human skin, relative
to the administered dose. For further details, see Example 1.
[0014] FIG. 2 shows the amount of tacrolimus found in different
layers of the skin (SC=stratum corneum; EP=vital epidermis;
DR=dermis; AK=hypodermis) 30 min, 300 min, and 1,000 min after
administration of a commercial formulation (Protopic.RTM. 0.1%) to
human skin, relative to the administered dose. For further details,
see Example 1.
[0015] FIG. 3 shows the penetration profiles of tacrolimus 30 min,
300 min, and 1,000 min after administration as an SFA-based
formulation to human skin, respectively. For further details, see
Example 1.
[0016] FIG. 4 shows the penetration profiles of tacrolimus 30 min,
300 min, and 1,000 min after administration a commercial
formulation (Protopic.RTM. 0.1%) to human skin, respectively. For
further details, see Example 1.
[0017] FIG. 5 shows the concentration of D,L-.alpha.-tocopherol
found in different layers of the skin (SC=stratum corneum; EP=vital
epidermis; DR=dermis) 100 min after administration as SFA-based
formulation (SFA), Unguentum emulsificans aquosum DAB (WHS),
Basiscreme DAC (BC), Lanae alcoholum unguentum aquosum DAB (WWS).
For further details, see Example 2.
[0018] FIG. 6 shows the concentration of
betamethasone-17,21-dipropionate in different layers of the skin
(SC=stratum corneum; EP=vital epidermis; DR=dermis) 100 min after
administration as SFA-based formulation (SFA), Unguentum
emulsificans aquosum DAB (WHS), Basiscreme DAC (BC), Lanae
alcoholum unguentum aquosum DAB (WWS). For further details, see
Example 3.
DETAILED DESCRIPTION OF THE INVENTION
[0019] The invention provides a novel pharmaceutical composition
for use as a topical formulation which is to be administered to the
skin or a skin appendage. The composition comprises an effective
amount of an active ingredient and a semifluorinated alkane
according to formula RFRH or RFRHRF, wherein RF is a perfluorinated
hydrocarbon segment with 20 or less carbon atoms and RH is a
non-fluorinated hydrocarbon segment with 3 to 20 carbon atoms, and
in particular, wherein the perfluorinated segment is linear and
comprises from 4 to 12 carbon atoms, and/or the non-fluorinated
segment is linear and comprises from 4 to 8 carbon atoms.
[0020] The invention is based on the surprising discovery that the
semifluorinated alkanes (SFAs) as defined above are highly suitable
carriers for topically administered drugs and capable of delivering
such drugs very effectively to the layers of the skin below the
stratum corneum, i.e. the viable epidermis, but also to the dermis
and hypodermis. This was particularly unexpected in view of Hardung
(Doctoral Thesis, Albert-Ludwigs-University of Freiburg, Germany,
2008), who investigated the suitability of SFAs as carriers for
topical medications using e.g. testosterone as a model drug, and
who came to the conclusion that an SFA such as F6H8 (see below for
an explanation of the terminology of SFAs) does not affect an
improved penetration into the skin, interact with the stratum
corneum or exhibit any penetration-enhancing effect (p. 103, first
full paragraph). However, in spite of such discouraging statements
in the prior art, the inventors have further investigated the
impact of SFAs and SFA-based carriers on the delivery of drugs into
the deeper layers of the skin and nails using excised human skin
(in contrast to Hardung who used pig skin), and have now
surprisingly found that SFAs are indeed capable of enhancing the
penetration of drugs into the relevant skin layers, as will be
shown in more detail below.
[0021] As used herein, a pharmaceutical composition is any
composition comprising an active ingredient useful for the
diagnosis, prevention, management or therapy of a disease, symptom
or health condition and at least one carrier or excipient. A
topical formulation is a composition which is in a form suitable
for topical administration. In the present invention, the
composition is suitable for administration to the skin or a skin
appendage of a subject, which subject may be a human or an animal.
The skin may be intact skin or injured, bruised, damaged or
otherwise affected skin. A skin appendage is a structure derived
from the skin, and usually adjacent to it, such as a hair, a sweat
or sebaceous gland. Semifluorinated alkanes are linear or branched
alkanes some of whose hydrogen atoms have been replaced by
fluorine. In a preferred embodiment, the semifluorinated alkanes
(SFA's) used in the present invention are composed of at least one
non-fluorinated hydrocarbon segment and at least one perfluorinated
hydrocarbon segment. Particularly useful are SFA's which have one
non-fluorinated hydrocarbon segment attached to one perfluorinated
hydrocarbon segment, according to the general formula
F(CF.sub.2).sub.n(CH.sub.2).sub.mH, or two perfluorinated
hydrocarbon segments separated by one non-fluorinated hydrocarbon
segment, according to the general formula
F(CF.sub.2).sub.n(CH.sub.2).sub.m(CF.sub.2).sub.oF.
[0022] Another nomenclature which is used herein refers to the
above-mentioned SFA's having two or three segments as RFRH and
RFRHRF, respectively, wherein RF designates a perfluorated
hydrocarbon segment, RH designates a non-fluorinated segment.
Alternatively, the compounds may be referred to as FnHm and FnHmFo,
respectively, wherein F means a perfluorated hydrocarbon segment, H
means a non-fluorinated segment, and n, m and o is the number of
carbon atoms of the respective segment. For example, F3H3 is used
for perfluoropropylpropane. Moreover, this type of nomenclature is
usually used for compounds having linear segments. Therefore,
unless otherwise indicated, it should be assumed that F3H3 means
1-perfluoropropylpropane, rather than 2-perfluoropropylpropane,
1-perfluoroisopropylpropane or 2-perfluoroisopropylpropane.
[0023] Preferably, the semifluorinated alkanes according to the
general formulas F(CF.sub.2).sub.n(CH.sub.2).sub.mH and
F(CF.sub.2).sub.n(CH.sub.2).sub.m(CF.sub.2).sub.oF have segment
sizes ranging from 3 to 20 carbon atoms, i.e. n, m and o are
independently selected in the range from 3 to 20. SFAs which are
useful in the context of the present invention are also described
in EP-A 965 334, EP-A 965329 and EP-A 2110126, the disclosure of
which documents is incorporated herein.
[0024] In a further embodiment, the semifluorinated alkane is a
compound according to the formula RFRH, whose segments R.sub.F and
R.sub.H are linear and each--but independently from one
another--have from 3 to 20 carbon atoms. In particular, the
perfluorinated segment is linear and comprises from 4 to 12 carbon
atoms, and/or the non-fluorinated segment is linear and comprises
from 4 to 8 carbon atoms. Preferred SFA's include in particular the
compounds F4H5, F4H6, F4H8, F6H4, F6H6, F6H8, and F6H10. Presently
most preferred for carrying out the invention are F4H5, F4H6, F6H6
and F6H8.
[0025] Optionally, the composition may comprise more than one SFA.
It may be useful to combine SFA's, for example, in order to achieve
a particular target property such as a certain density, viscosity,
or solubilising capacity for a particular active ingredient. If a
mixture of SFA's is used, it is furthermore preferred that the
mixture comprises at least one of F4H5, F4H6, F4H8, F6H4, F6H6,
F6H8, and F6H10, and in particular one of F4H5, F4H6, F4H8, F6H6
and F6H8. In another embodiment, the mixture comprises at least two
members selected from F4H5, F4H6, F4H8, F6H4, F6H6, F6H8, and
F6H10, and in particular at least two members selected from F4H5,
F6H6, F4H8, and F6H8. Furthermore, mixtures of a semifluorinated
alkane, e.g. F4H5, with a perfluorinated compound, such as
perfluorooctylbromide or perfluorodecalin, or with another oily
material are also contemplated. Other oily materials would, for
example, include silicone oils, triglycerides (e.g. native or
synthetic medium-chain triglycerides), or compounds such as
isopropyl myristate. In some preferred embodiments, however,
perfluorinated compounds are absent.
[0026] Liquid SFA's are chemically and physiologically inert,
colourless and stable. Their typical densities range from 1.1 to
1.7 g/cm.sup.3, and their surface tension may be as low as 19 mN/m.
SFA's of the RFRH type are insoluble in water but also somewhat
amphiphilic, with increasing lipophilicity correlating with an
increasing size of the non-fluorinated segment. Again, for
practising the current invention, an SFA having a density of at
least 1.2 g/cm.sup.3 should be selected.
[0027] Liquid SFA's of the RFRH type are being used commercially
for unfolding and reapplying a retina, for long-term tamponade as
vitreous humor substitute (H. Meinert et al., European Journal of
Ophthalmology, Vol. 10(3), pp. 189-197, 2000), and as wash-out
solutions for residual silicon oil after vitreo-retinal surgery.
Experimentally, they have also been used as blood substitutes (H.
Meinert et al., Biomaterials, Artificial Cells, and Immobilization
Biotechnology, Vol. 21(5), pp. 583-95, 1993). These applications
have established SFA's as physiologically well tolerated compounds.
On the other hand, SFA's have not been used as excipients in
approved drug products as of today.
[0028] For allowing convenient administration to the skin or skin
appendages, the composition is preferably liquid or semi-solid. As
used herein, semi-solid means that a material behaves like a solid
upon the exertion of low shear force, but above a certain force
threshold, the so-called "yield point", it behaves like a viscous
fluid. Whether liquid or semi-solid, the composition may represent
a single phase (i.e. a solution), or consist of two or more
phases.
[0029] In a particular embodiment, for example, the composition is
in the form of an emulsion. As used herein, an emulsion is a system
comprising a dispersed (or inner, or emulsified, or discontinuous)
liquid phase within a continuous (or outer, or coherent) liquid or
semisolid phase. The two phases are not miscible. In an
O/W-emulsion (also referred to as oil-in-water emulsion), a
water-immiscible organic liquid phase, which does not have to be an
"oil" by any specific definition, is dispersed in a water-miscible
continuous phase which may or may not be substantially comprised of
water itself. Within emulsions, O/W-emulsions are preferred for
carrying out the invention.
[0030] In another embodiment, the composition is in the form of a
microemulsion. A microemulsion is a clear, thermodynamically
stable, optically isotropic mixture of a lipophilic component, a
hydrophilic component, and an amphiphilic component. Typically, a
microemulsion forms spontaneously when the components are combined
and mixed with each other, without requiring high energy input as
is normally required for the formation of an "ordinary" emulsion.
Microemulsions may have a colloidal lipophilic phase dispersed in a
hydrophilic phase, or a hydrophilic phase colloidally dispersed in
a lipophilic phase. The size of the dispersed phases is usually in
the range from about 5 nm to about 400 nm, and most often below
about 200 nm. In one of the preferred embodiments of the invention,
the particle size is from about 5 nm to about 100 nm. In terms of
its rheological properties, the microemulsion may be in the form of
a liquid or a gel, i.e. in liquid or semisolid form. In a preferred
embodiment, the microemulsion is in liquid form.
[0031] For microemulsions according to the invention, it is
preferred to use an oil phase comprising from about 5 to about 95
wt.-% of SFA, and more preferably from about 10 to about 80 wt.-%
of SFA, the remainder of the oil phase being another oil such as
isopropylmyristate. With respect to the incorporation of aqueous
components, surfactants and optionally cosurfactants, commonly
known constituents of micro emulsions may be used to formulate the
composition.
[0032] The composition, whether formulated as a solution,
microemulsion or conventional emulsion, may contain any further
pharmaceutically acceptable ingredients as required or useful in
view of the intended application. In a particular embodiment, an
additional solvent or co-solvent may be incorporated, for example
in order to achieve a higher solubility for a specific active
ingredient, to modify the viscosity or stability of the
formulation, or to further enhance the cutaneous penetration of the
active ingredient. Such co-solvent should of course be selected in
type, quality and amount such as to maintain the physiological
tolerability of the formulation. Potentially suitable co-solvents
include ethanol, acetone, ethyl acetate, isopropyl alcohol,
glycerol, propylene glycol, pentylene glycol, polyethylene glycol,
liquid paraffin, triglyceride oils, hydrofluorocarbons such as HFA
134a and/or HFA 227, and liquid mono- or diglycerides. Among these,
ethanol and pentylene glycol are among the particularly preferred
solvents. It has been found that relatively small amounts of
ethanol may substantially modify the solubilising properties of
SFAs and allow the incorporation of a number of active ingredients
at higher concentrations. For example, the composition may comprise
up to about 10 wt.-% of ethanol, or up to about 5 wt.-% of ethanol.
Even at a low concentration of up to about 3 wt.-%, ethanol may be
a very useful additive in the composition, depending on the
specific drug substance to be delivered. Pentylene glycol is also
very useful as co-solvent in general and, in particular, it has
been found that its incorporation is advantageous in the
formulation of microemulsions.
[0033] Moreover, the composition may comprise one or more
stabilisers, surfactants (in particular if the composition is in
the form of an emulsion or microemulsion), cosurfactants (in
particular if it is in the form of a microemulsion), colouring
agents, antioxidants (for example, .alpha.-tocopherol), thickeners
(viscosity-increasing agents such as bentonite), and
fragrances.
[0034] If a surfactant is present, it may, for example, be selected
from physiologically acceptable phospholipids (such as
phosphatidylcholines); nonionic surfactants such as fatty alcohols,
pegylated glycerides, pegylated fatty acids, pegylated fatty
alcohols, pegylated sorbitan fatty acid esters, and poloxamers;
anionic surfactants such as sodium lauryl sulphate, docusate
sodium, and sodium deoxycholate.
[0035] The composition may be prepared by commonly known techniques
for the manufacture of pharmaceutical solutions, emulsions, and
microemulsions. Depending on their consistency and specific use,
they may be presented in bottles, spray bottles, or tubes.
[0036] The active ingredient incorporated within the composition
may, in principle, be selected from drug substances which are
useful for the prevention, management, or therapy of a cutaneous
disease or condition.
[0037] In one of the specific embodiments, the active ingredient is
poorly water-soluble. In particular, it water solubility is not
more than about 1 mg/mL. In other preferred embodiments, the water
solubility is not higher than about 0.1 mg/mL, or not more than
about 10 .mu.g/mL, respectively. The invention is particularly
useful for delivering such active ingredients because it allows the
administration of effective doses in relatively small volumes,
which is at least partly due to the surprisingly high
solubilisation capacity of semifluorinated alkanes for many poorly
water-soluble drug substances.
[0038] For the avoidance of doubt, it is affirmed that the
invention is not restricted to poorly water-soluble drug
substances. It has been found that certain bioactive agents have
substantial aqueous solubility, but can also be advantageously
formulated in SFA-based carriers.
[0039] The active ingredient may be selected from drug substances
useful for the prevention and in particular for the management and
therapy of cutaneous diseases and conditions, such as psoriasis,
dermatitis, erythema, acne, actinic keratosis, verrucae, and
rosacea. The invention appears generally useful for delivering drug
substances of various therapeutic categories to the deep layers of
the skin, i.e. to the vital epidermis, the dermis, and/or to the
hypodermis which may also be understood as being part of the
integumentary system. Topical administration of the compositions to
the skin may result in the delivery of the drug substance to the
stratum corneum, as well as penetration through the strateum
corneum and delivery of the active drug substance to these deeper
skin layers. Cutaneous diseases or conditions may affect the
stratum corneum, as well as one or more of the deeper skin layers.
The composition may thus be used for the prevention or treatment of
diseases or conditions that affect also the vital epidermis, the
dermis and/or the hypodermis. In one of the specific embodiments,
the composition is used in the therapy of psoriasis, and
incorporates an active ingredient which may be used to control
psoriasis or a symptom thereof. Such active ingredient may, for
example, be an immunosuppressant drug, such as a macrolide
immunosuppressant. Examples of potentially suitable macrolide
immunosuppressants include tacrolimus, sirolimus, everolimus,
tacrolimus, pimecrolimus, ridaforolimus, temsirolimus, zotarolimus,
and ciclosporin A; or retinoids such as retinol, retinal,
tretinoin, isotretinoin, alitretinoin, etretinate, acitretin,
tazarotene, bexarotene and adapalene. Tacrolimus is one of the
particularly preferred drugs in this group. It has been found by
the inventors that tacrolimus can be very effectively (i.e. faster
and deeper than using conventional formulations) delivered to the
deep and viable layers of the skin using the composition of the
invention (see Example 1).
[0040] As illustrated in Example 1, the composition of the
invention may be used to effectively deliver an active ingredient
such as a macrolide immunosuppressant, as for example tacrolimus,
to the deeper layers of the skin. For example, at least about 5% of
the topically administered amount of drug may be delivered to the
vital epidermis within only about 30 minutes. The composition may
also be used to deliver at least 5% of the topically administered
drug to the dermis within about 30 minutes, or even at least about
10% of the administered dose. Also in terms of delivery to the
hypodermis, the composition may be used to deliver at least 5% of
the topically administered amount of drug to this layer within the
same period of time, or even 10% or more.
[0041] Taking into account the typical thickness of the respective
skin layers, the composition may be used to deliver within about 30
minutes at least about 15% of the topically administered drug dose
to a depth of at least about 10 .mu.m. In other embodiments, at
least about 20% of the dose is delivered to a depth of at least
about 10 .mu.m. The composition may also be used to deliver at
least about 10% of the topically administered drug to a depth of
100 .mu.m or more within about 30 minutes; or at least about 15% or
at least about 20% of the dose, respectively.
[0042] Another therapeutic indication in which it is of great
importance that the therapeutic agent penetrates the deeper layers
of the affected skin is cutaneous mycosis, such as athlete's foot,
candidal vulvovaginitis, and other fungal infections of the
integument. in the context, the invention may be used by preparing
and administering an SFA-based composition comprising a suitable
topically active antifungal agent, in particular an azole such as
clotrimazole, ketoconazole, or miconazole; or an allylamine, such
as terbinafine, naftifine, or butenafine.
[0043] In a further embodiment, the disease to be treated is acne,
such as acne vulgaris or other forms of acneiform eruptions. In
this case, the active ingredient may, for example, be selected from
retinoids, such as retinol, retinal, tretinoin, isotretinoin,
alitretinoin, etretinate, acitretin, tazarotene, bexarotene and
adapalene; antiinfective agents such as azithromycin, erythromycin,
clindamycin, or minocycline; or spironolactone.
[0044] According to another embodiment, the invention is used in
the treatment of actinic keratosis, which is a premalignant
condition of the skin characterised by the presence of thick,
scaly, or crusty patches. In this case, the active ingredient may
be selected from NSAIDs such as diclofenac, ketoprofene and
flurbiporofene, but also 5-fluorouracil and imiquimod.
[0045] Moreover, the invention is suitable for the treatment of
viral infections of the skin, such as herpes simplex, herpes
zoster, and varicella. For this indication, an antiviral compound
is incorporated in the SFA-based composition, such as acyclovir,
penciclovir, or docosanol.
[0046] In a further embodiment, the composition of the invention
comprises a local anaesthetic agent such as benzocaine, butamben,
dibucaine, lidocaine, oxybuprocaine, pramoxine, proparacaine,
proxymetacaine, and tetracaine. Such composition may be used to
relieve pain or itching caused by conditions such as sunburn or
other minor burns, insect bites or stings, or in preparation of
minor surgical procedures.
[0047] A large number of cutabeous diseases and conditions involve
symptoms related to inflammatory responses, such as most forms of
dermatitis, including atopic dermatitis, seborrhoeic dermatitis,
allergic dermatitis, contact dermatis and the like, but also
certain forms of pruritus, psoriasis, allergies, nummular eczema,
xerotic eczema, lichen sclerosis, lichen planus, discoid lupus,
chapped feet, lichen simplex chronicus, poison ivy reactions,
alopecia areata, nummular eczema etc. Often these conditions
require therapy or symptomatic control with topical
corticosteroids, which can also be formulated and administered
advantageously according to the invention. Suitable corticosteroid
which may be incorporated in an SFA-based composition include
amcinonide, betamethasone dipropionate, clobetasol propionate,
desonide, desoximetasone, diflorasone diacetate, fluocinolone
acetonide, fluocinonide, flurandrenolide, fluticasone propionate,
halcinonide, halobetasol proprionate, hydrocortisone,
hydrocortisone butyrate, hydrocortisone valerate, mometasone
furoate, prednicarbate, and triamcinolone acetonide.
[0048] The invention is further illustrated by the following
examples.
EXAMPLES
Example 1
[0049] Tacrolimus was dissolved in a liquid carrier comprising F6H8
and 3.8 wt.-% ethanol to obtain a clear solution having a
tacrolimus concentration of 1 mg/mL.
[0050] Excised human skin was obtained from a breast reduction
surgical centre. Skin samples were washed with isotonic sodium
chloride solution. The subcutaneous adipose layers were removed.
Circular pieces of 20 mm in diameter (3.14 cm.sup.2) were punched
out, supported by filter gauze, and mounted in FRANZ diffusion
cells in such a way that the dermal side was in contact with the
acceptor fluid (PBS pH 7.4), which was continuously stirred and
kept at 32.degree. C. Loss through evaporation was avoided by means
of a glass lid.
[0051] On each skin sample (epidermal side), an amount of 20 .mu.L
of the tacrolimus solution was placed and spread out evenly. After
a testing time of 30 min, 300 min, or 1,000 min, respectively, the
remaining tacrolimus solution on the samples was collected and the
skin samples were removed. From each specimen, three small punch
biopsies of 6 mm diameter (0.2827 cm.sup.2) were obtained and
frozen. At -40.degree. C., the punch biopsies were cryomicrotomised
as follows: [0052] 1 slice of 10 .mu.m thickness, corresponding to
the stratum corneum [0053] 4 slices of 20 .mu.m each, corresponding
to the vital epidermis [0054] 5.times.5 slices of 40 .mu.m each,
corresponding to 5 layers of dermis
[0055] All slices and the remaining stumps were extracted, and the
amount of tacrolimus was determined by HPLC-MS. Moreover, the
acceptor fluid and the fluid removed from the stratum corneum after
each test were also analysed for tacrolimus. Each test was
performed in triplicate, using skin from three different
donors.
[0056] For comparison, a similar series of experiments using a
commercial tacrolimus ointment (Protopic.RTM. 0.1%, Astellas
Pharma, 20 mg per skin sample and FRANZ cell) was conducted.
[0057] In result, it was found that the penetration of tacrolimus
into the relevant skin layers was clearly superior in the case of
the solution according to the invention. For example, already after
30 minutes approx. 9% of the administered dose was found in the
vital epidermis, and approx. 12% was found in the layers of the
dermis (see FIG. 1). For comparison, the commercial formulation
delivered only about 2.5% of the dose to the vital epidermis and
only about 5% to the dermis during the same period of time (see
FIG. 2). After 1,000 minutes, the amount in the dermis was about
30% of the dose in the case of the solution of the invention (see
FIG. 1), but only about 12.5% in the case of the commercial
preparation (see FIG. 2). At all times, the penetration depth was
much higher for the composition of the invention (see FIG. 3) than
for the commercial product (see FIG. 4).
Example 2
[0058] A solution of radiolabeled D,L-.alpha.-tocopherol in F6H8
having a concentration of 10 mg/mL was prepared and used for a
series of skin penetration experiments in analogy to Example 1,
using excised human skin, with a few differences to the procedure
of Example 1 as described below.
[0059] The amount of the formulation applied to each skin sample
was 6 mg. The test period was 100 min. After the testing period,
the stratum corneum of each sample was removed by the film
stripping method (20 strips). Slices of the vital epidermis and the
dermis were however obtained by microtomy at -40.degree. C.
[0060] For comparison, three pharmacopoeial ointment formulations
incorporating the same concentration of D,L-.alpha.-tocopherol were
prepared and tested: "Unguentum emulsificans aquosum" (DAB),
"Basiscreme" (DAC), and "Lanae alcoholum unguentum aquosum"
(DAB).
[0061] In result, it was surprising to find that the SFA-based
formulation resulted in a much higher concentration of tocopherol
in the vital epidermis than the three conventional formulations
(see FIG. 5).
Example 3
[0062] The series of experiments of Example 2 were repeated in
analogy, but using radiolabeled betamethasone-17,21-dipropionate as
active ingredient at a concentration of 1 mg/mL instead of
tocopherol. Another difference was that the SFA-based formulation
of the drug contained 2.5 wt.-% ethanol.
[0063] Here it was found that the drug concentration in the skin
layers was highest in the case of the SFA-based formulation of the
invention, with a clear difference between the tested formulations
with respect to the stratum corneum and the vital epidermis, but
somewhat less differentiation in the dermis (see FIG. 6).
Example 4
[0064] An SFA-based microemulsion with tacrolimus was prepared.
Basically, 10 mg of tacrolimus were dissolved in 1.5 mg of
Tween.RTM. 80 and 2 g of Brij.RTM. 30. Then 2 g of 1,2-pentandiole
were added, followed by 0.3 g of F6H8 and 0.7 g of isopropyl
myristate. After gentle stirring, 4 g of water were added and the
mixture was homogenised until it had a transparent appearance.
* * * * *